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1.
Mutat Res ; 608(2): 163-8, 2006 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-16835015

RESUMEN

To test hypotheses on the origins of p53 mutations in human tumors, novel strategies are needed for generating mutation spectra experimentally. To this end we developed an assay employing Hupki (Human p53 knock-in) mouse embryonic fibroblasts (HUFs). Here we examine p53 mutations induced by aristolochic acid I (AAI)), the carcinogen probably responsible for Chinese herbal nephropathy. Six immortalized cultures (cell lines) from 18 HUF primary cultures exposed at passage 1 for 48 h to 50 microM AAI harbored p53 mutations in the human DNA binding domain sequence of the Hupki p53 tumor suppressor gene. The most frequently observed mutation was A to T transversion, corroborating our previous mutation study with AAI, and consistent with the presence of persistent AAI-adenine adducts found both in DNA of exposed patients and in DNA of AAI-exposed HUF cells. One of the mutations was identical in position (codon 139) and base change (A to T on the non-transcribed strand) to the single p53 mutation that has thus far been characterized in a urothelial tumor of a nephropathy patient with documented AAI exposure. Of the seven p53 mutations identified thus far in >60 HUF cell lines that immortalized spontaneously (no carcinogen treatment), none were A:T to T:A transversions. In addition, no A to T substitutions were identified among the previously reported set of 18 mutations in HUF cell lines derived from B(a)P treatment in which transversions at G:C base pairs predominated.


Asunto(s)
Ácidos Aristolóquicos/toxicidad , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/genética , Genes p53/efectos de los fármacos , Mutación Puntual , Animales , Secuencia de Bases , Línea Celular Transformada , Codón/genética , ADN/genética , Aductos de ADN/análisis , Aductos de ADN/genética , Análisis Mutacional de ADN , Humanos , Ratones , Ratones Transgénicos , Mutágenos/toxicidad
2.
Lancet ; 358(9292): 1515-6, 2001 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-11705569

RESUMEN

We have previously reported occurrence of a specific type of nephropathy due to ingestion of Chinese herbs (Chinese herbal nephropathy [CHN]) in two patients in the UK. These cases highlighted the role of aristolochic acid in causing this nephropathy, which was first described in a Belgian cohort. We now report development of invasive transitional cell carcinoma of the urinary tract associated with the presence of aristolochic acid-DNA adducts in one of these patients. This work clearly shows the carcinogenic potential of aristolochic acid in this new type of nephropathy.


Asunto(s)
Ácidos Aristolóquicos , Carcinógenos/efectos adversos , Carcinoma de Células Transicionales/inducido químicamente , Medicamentos Herbarios Chinos/efectos adversos , Fenantrenos/efectos adversos , Neoplasias Ureterales/inducido químicamente , Carcinoma de Células Transicionales/patología , Femenino , Humanos , Fallo Renal Crónico/inducido químicamente , Persona de Mediana Edad , Neoplasias Ureterales/patología
3.
Am J Kidney Dis ; 38(5): E26, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11684578

RESUMEN

The causal role of aristolochic acid (AA) in the so-called Chinese herbs nephropathy (CHN) has been conclusively demonstrated only in the Belgian epidemic. We report a biopsy-proven hypocellular interstitial fibrosing nephropathy in a Chinese patient who had ingested a Chinese herbal preparation bought in Shanghai. The identification of AA in the preparation and of AA-DNA adducts in the kidney tissue unequivocally demonstrates, for the first time, the causal role of AA outside the Belgian epidemic. Because the ingested preparation is very popular in China as an over-the-counter product, our observation raises the possibility that many such cases due to AA might be currently unrecognized in China. AA should be banned from herbal preparations worldwide. All cases of the so-called CHN, in which the causal role of AA has been thoroughly documented, should be further identified as aristolochic acid nephropathy (AAN). The term phytotherapy-associated interstitial nephritis (PAIN) might refer to the other cases associated with phytotherapy without identification, as yet, of the causal agent.


Asunto(s)
Ácidos Aristolóquicos , Fenantrenos/efectos adversos , Insuficiencia Renal/inducido químicamente , Aductos de ADN , Medicamentos Herbarios Chinos/efectos adversos , Femenino , Humanos , Riñón/efectos de los fármacos , Riñón/patología , Riñón/fisiopatología , Persona de Mediana Edad , Terminología como Asunto
4.
Mutat Res ; 494(1-2): 143-50, 2001 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-11423353

RESUMEN

Chinese herbs nephropathy (CHN), a unique type of nephropathy has been associated with the intake of weight-reducing pills containing the Chinese herb Aristolochia fangchi. Moreover, an association between the use of A. fangchi and urothelial cancer in CHN patients has been reported indicating that aristolochic acid (AA) the major alkaloid of A. fangchi might be the causal agent. Similarities of CHN to the Balkan endemic nephropathy (BEN) have led to the hypothesis of a common etiological agent for both diseases. Evidence has accumulated that BEN is an environmentally-induced disease strongly associated with the fungal mycotoxin ochratoxin A (OTA). Both, AA and OTA are nephrotoxic and carcinogenic and induce the formation of DNA adducts. As OTA has been suspected as fungal contaminant in the herbal batches used for the preparation of the weight-reducing pills we analysed tissues from CHN patients by the 32P-postlabeling procedure for the presence of DNA adducts related to both OTA and AA exposure. Whereas, AA-specific DNA adducts were detected in all five urinary tract tissues from five patients (total RAL: 32-251 adducts per 10(9) nucleotides), OTA-related DNA adducts were detectable in two kidneys and one ureter only (total RAL: 1.5-3.7 adducts per 10(9) nucleotides). Thus, OTA-related DNA adduct levels were about 50 times lower than AA-DNA adduct levels. In female and male rats that were treated with the slimming regimen in the same way like the CHN patients except that the amount of Chinese herbs was 10 times higher, AA-DNA adducts were found in kidney tissues (total RAL ranging from 51 to 83 adducts per 10(9) nucleotides) but adducts derived from OTA were not observed. These results demonstrate that OTA-related DNA adducts do not play a key role in CHN or CHN-associated urothelial cancer.


Asunto(s)
Fármacos Antiobesidad/efectos adversos , Ácidos Aristolóquicos , Aductos de ADN/análisis , Medicamentos Herbarios Chinos/efectos adversos , Ocratoxinas/toxicidad , Fenantrenos/toxicidad , Insuficiencia Renal/inducido químicamente , Adulto , Animales , Nefropatía de los Balcanes/etiología , Bélgica/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Micotoxinas/toxicidad , Ratas , Ratas Wistar , Insuficiencia Renal/epidemiología , Insuficiencia Renal/etiología
5.
Gen Physiol Biophys ; 20(4): 375-92, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11989648

RESUMEN

Aristolochic acid (AA), a naturally occurring nephrotoxin and carcinogen, has been found to be implicated in an unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN), and associated with the development of urothelial cancer in CHN patients. Understanding, which enzymes are involved in AA activation and/or detoxication is important in the assessment of individual susceptibility of humans to this natural carcinogen. Using the nuclease P1 version of the 32P-postlabeling assay we examined the ability of microsomal NADPH: CYP reductase to activate AA to metabolites forming DNA adducts. Renal and hepatic microsomes, containing NADPH:CYP reductase, generated AA-DNA adduct patterns reproducing those found in renal tissues in patients suffering from a renal fibrosis CHN and urothelial cancer. 7-(Deoxyadenosin-N6-yl)aristolactam I, 7-(deoxyguanosin-N2-yl)aristolactam I and 7-(deoxyadenosin-N6-yl)aristolactam II were identified as AA-DNA adducts formed by AAI. Two AA-DNA adducts, 7-(deoxyguanosin-N2-yl) aristolactam II and 7- (deoxyadenosin-N6-yl) aristolactam II, were generated from AAII. According to the structures of the DNA adducts identified, nitroreduction is the crucial pathway in the metabolic activation of AA. The identity of NADPH: CYP reductase as activating enzyme in microsomes has been proved with different cofactors and an enzyme inhibitor. Alpha-lipoic acid, a selective inhibitor of NADPH: CYP reductase, significantly decreased the amount of the adducts formed by microsomes. Likewise, only a cofactor of the enzyme, NADPH, supported the DNA adduct formation of AAI and AAII, while NADH was ineffective. These results demonstrate an involvement of NADPH: CYP reductase in the activation pathway of AAI and AAII in the microsomal system. Moreover, using the purified enzyme, the participation of this enzyme in the formation of AA-DNA adducts was confirmed. The results presented here are the first report demonstrating a reductive activation of natural nitroaromatic compounds, AA, by NADPH: CYP reductase.


Asunto(s)
Ácidos Aristolóquicos , Carcinógenos , Aductos de ADN , ADN/metabolismo , Medicamentos Herbarios Chinos/uso terapéutico , Activación Enzimática , NADPH-Ferrihemoproteína Reductasa/metabolismo , Fenantrenos , Animales , Bovinos , Relación Dosis-Respuesta a Droga , Riñón/patología , Hígado/patología , Masculino , Microsomas Hepáticos/metabolismo , Modelos Químicos , Ratas , Ratas Wistar , Factores de Tiempo
6.
N Engl J Med ; 342(23): 1686-92, 2000 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-10841870

RESUMEN

BACKGROUND: Chinese-herb nephropathy is a progressive form of renal fibrosis that develops in some patients who take weight-reducing pills containing Chinese herbs. Because of a manufacturing error, one of the herbs in these pills (Stephania tetrandra) was inadvertently replaced by Aristolochia fangchi, which is nephrotoxic and carcinogenic. METHODS: The diagnosis of a neoplastic lesion in the native urinary tract of a renal-transplant recipient who had Chinese-herb nephropathy prompted us to propose regular cystoscopic examinations and the prophylactic removal of the native kidneys and ureters in all our patients with end-stage Chinese-herb nephropathy who were being treated with either transplantation or dialysis. Surgical specimens were examined histologically and analyzed for the presence of DNA adducts formed by aristolochic acid. All prescriptions written for Chinese-herb weight-reducing compounds during the period of exposure (1990 to 1992) in these patients were obtained, and the cumulative doses were calculated. RESULTS: Among 39 patients who agreed to undergo prophylactic surgery, there were 18 cases of urothelial carcinoma (prevalence, 46 percent; 95 percent confidence interval, 29 to 62 percent): 17 cases of carcinoma of the ureter, renal pelvis, or both and 1 papillary bladder tumor. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia, and two had normal urothelium. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The cumulative dose of aristolochia was a significant risk factor for urothelial carcinoma, with total doses of more than 200 g associated with a higher risk of urothelial carcinoma. CONCLUSIONS: The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high.


Asunto(s)
Ácidos Aristolóquicos , Carcinógenos/efectos adversos , Medicamentos Herbarios Chinos/efectos adversos , Fallo Renal Crónico/inducido químicamente , Fenantrenos/efectos adversos , Neoplasias Urológicas/inducido químicamente , Fármacos Antiobesidad/efectos adversos , Carcinógenos/análisis , Carcinógenos/metabolismo , Aductos de ADN/análisis , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Riñón/patología , Fallo Renal Crónico/patología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Ocratoxinas/análisis , Fenantrenos/análisis , Fenantrenos/metabolismo , Prevalencia , Factores de Riesgo , Uréter/patología , Neoplasias Urológicas/patología , Urotelio/patología
7.
Exp Toxicol Pathol ; 51(4-5): 421-7, 1999 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10445409

RESUMEN

Aristolochic acid (AA) a naturally occuring nephrotoxin and carcinogen is implicated in a unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN). We identified AA-specific DNA adducts in kidneys and in a ureter obtained from CHN patients after renal transplantation. AA is a plant extract of aristolochia species containing AA I as the major component. Aristolactams are the principal detoxication metabolites of AA, which were detected in urine and faeces from animals and humans. They are activated by cytochrome P450 (P450) and peroxidase to form DNA adducts. Using the 32P-postlabelling assay we investigated the formation of DNA adducts by aristolactam I in these two activation systems. A combination of two independent chromatographic systems (ion-exchange chromatography TLC and reversed-phase HPLC) with reference compounds was used for the identification of adducts. Aristolactam I activated by peroxidase led to the formation of several adducts. Two major adducts were identical to adducts previously observed in vivo. 7-(deoxyguanosin-N2-yl)aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)aristolactam I (dA-AAI) were formed in DNA during the peroxidase-mediated one-electron oxidation of aristolactam I. Aristolactam I activated by P450 led to one major adduct and four minor ones. Beside the principal AA-DNA adducts identified recently in the ureter of one patient with CHN, an additional minor adduct was detected, which was found to have indistinguishable chromatographic properties on TLC and HPLC from the major adduct formed from aristolactam I by P450 activation. Thus, this minor AA-adduct might be evolved from the AAI detoxication metabolite (aristolactam I) by P450 activation. These results indicate a potential carcinogenic effect of aristolactam I in humans.


Asunto(s)
Ácidos Aristolóquicos , Aductos de ADN/metabolismo , Dioxoles/metabolismo , Medicamentos Herbarios Chinos/efectos adversos , Indoles/metabolismo , Enfermedades Renales/inducido químicamente , Fenantrenos/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Sistema Enzimático del Citocromo P-450/metabolismo , ADN/metabolismo , Aductos de ADN/análisis , Dioxoles/análisis , Fibrosis , Peroxidasa de Rábano Silvestre/metabolismo , Humanos , Peróxido de Hidrógeno/farmacología , Indoles/análisis , Masculino , Ratas , Ratas Sprague-Dawley , Uréter/química
8.
Arch Toxicol ; 72(11): 738-43, 1998 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9879812

RESUMEN

Chinese herbs nephropathy (CHN), a rapidly progressive interstitial fibrosis of the kidney, has been described in approximately 100 young Belgian women who had followed a slimming regimen containing some Chinese herbs. In 4 patients multifocal transitional cell carcinomas (TCC) were observed. Aristolochic acid (AA), suspected as the causal factor of CHN, is a well known carcinogen but its ability to induce fibrosis has never been demonstrated. The objective of this study was to evaluate the latter using doses of AA, durations of intoxication and delays of sacrifice known to yield tumours in rats. We also tested the hypothesis that a possible fibrogenic role of AA was enhanced by the other components of the slimming regimen. Male and female rats were treated orally with 10 mg isolated AA/kg per day for 5 days/week, or with approximately 0.15 mg AA/ kg per day 5 days/week contained in the herbal powder together with the other components prescribed in the slimming pills for 3 months. The animals were killed respectively 3 and 11 months later. At sacrifice, animals in both groups had developed the expected tumours but not fibrosis of the renal interstitium. Whether the fibrotic response observed in man is due to species and/or strain related differences in the response to AA or to other factors, remains to be determined. Interestingly, despite the addition of fenfluramine and diethylpropion, two drugs incriminated in the development of valvular heart disease, no cardiac abnormalities were observed.


Asunto(s)
Fármacos Antiobesidad/toxicidad , Ácidos Aristolóquicos , Fibrina/efectos de los fármacos , Nefritis Intersticial/inducido químicamente , Fenantrenos/toxicidad , Neoplasias Gástricas/inducido químicamente , Animales , Carcinógenos/toxicidad , Medicamentos Herbarios Chinos/química , Femenino , Fibrina/metabolismo , Masculino , Ratas , Ratas Wistar
9.
Carcinogenesis ; 18(5): 1063-7, 1997 May.
Artículo en Inglés | MEDLINE | ID: mdl-9163697

RESUMEN

Recently, we reported that aristolochic acid (AA) a naturally occurring nephrotoxin and carcinogen is implicated in a unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN). Indeed, we identified the principal aristolochic acid-DNA adduct in the kidney of five such patients. We now extend these observations and demonstrate the presence of additional AA-DNA adducts by the 32P-post-labelling method not only in the kidneys, but also in a ureter obtained after renal transplantation. Using the nuclease P1 version of the assay not only the major DNA adduct of aristolochic acid, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), but also the minor adducts, 7-(deoxyguanosin-N2-yl)-aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)-aristolactam II (dA-AAII) were detected, and identified by cochromatographic analyses with TLC and HPLC. Quantitative analyses of six kidneys revealed relative adduct levels from 0.7 to 5.3/10(7) for dA-AAI, from 0.02 to 0.12/10(7) for dG-AAI and 0.06 to 0.24/ 10(7) nucleotides for dA-AAII. The detection of the dA-AAII adduct is consistent with the occurrence of aristolochic acid II (AAII) in the herb powder imported under the name of Stephania tetrandra and confirms that the patients had indeed ingested the natural mixture of AAI and AAII. 32P-post-labelling analyses of further biopsy samples of one patient showed the known adduct pattern of AA exposure not only in the kidney, but also in the ureter, whereas in skin and muscle tissue no adduct spots were detectable. In an attempt to explain the higher level of the dA-AAI adduct compared to the dG-AAI adduct level in renal tissue even 44 months after the end of regimen, the persistence of these two purine adducts was investigated in the kidney of rats given a single oral dose of pure AAI. In contrast to the dG-AAI adduct, the dA-AAI adduct exhibited a lifelong persistence in the kidney of rats. Our data demonstrate that AA forms DNA adducts in human tissue by the same activation mechanism(s) reported from animal studies. Thus, the carcinogenic/mutagenic activity of AA observed in animals could also be responsible for the urothelial cancers observed in two of the CHN patients.


Asunto(s)
Ácidos Aristolóquicos , Aductos de ADN , Medicamentos Herbarios Chinos/efectos adversos , Enfermedades Renales/genética , Fenantrenos/química , Adulto , Animales , Aductos de ADN/metabolismo , Femenino , Humanos , Enfermedades Renales/inducido químicamente , Masculino , Persona de Mediana Edad , Ratas , Ratas Wistar , Factores de Tiempo
10.
Cancer Res ; 56(9): 2025-8, 1996 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-8616845

RESUMEN

A unique type of rapidly progressive renal fibrosis, designated Chinese herbs nephropathy (CHN), has been described in young Belgian women who had followed a slimming regimen including recently introduced Chinese herbs (Stephania tetrandra and Magnolia officinalis). Aristolochic acid (AA), a known nephrotoxin and carcinogen, was suspected as its causal factor. To substantiate this hypothesis, renal tissue from five patients with CHN and six patients with other renal diseases was analyzed for the presence of AA-derived DNA adducts, a described biomarker of AA exposure associated with its carcinogenic and mutagenic activity. Using the 32P-postlabeling method, a major distinct DNA adduct spot was found in all five cases of CHN and identified by cochromatographic analyses with authentic markers as the deoxyadenosine adduct of AA-I [7-(deoxyadenosin-N6-yl)-aristolactam I], the major component of the plant extract AA. This DNA adduct was absent in the six control cases. The 7-(deoxyadenosin-N6-yl)-aristolactam I adduct levels in CHN ranged from 0.7 to 5.3/10(7) nucleotides. Our data demonstrate that AA is implicated in CHN. They suggest a mechanism for the urothelial atypia and cancers observed in this disease and raise the possibility that a DNA mutation is responsible for the kidney-destructive fibrotic process.


Asunto(s)
Ácidos Aristolóquicos , Aductos de ADN , Medicamentos Herbarios Chinos/efectos adversos , Enfermedades Renales/inducido químicamente , Riñón/efectos de los fármacos , Fenantrenos/efectos adversos , Adulto , Femenino , Humanos , Riñón/metabolismo , Enfermedades Renales/metabolismo , Fenantrenos/metabolismo
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